Nearly 11% (approximately 225,000 a year) of all pregnancies in the United States result in pre-term delivery. Such results in a significant incidence of perinatal morbidity and mortality. Despite major advances in neonatal care, retention of the fetus in utero is preferred in most instances. However, the desire to prolong intrauterine development must be balanced against the risks of continued pregnancy to both the mother and fetus, as well as the risks of concurrently available forms of pharmacological intervention. In general, the use of tocolytic agents to prolong pregnancy is reserved for those cases where the gestational age is greater than 20 weeks and less than 34 to 36 weeks.
There are several indications for, and contraindications to, the clinical use of agents that inhibit labor by inhibiting uterine contractions. The clearest indications for such agents are (1) to delay or prevent premature parturition in selected individuals and (2) to slow or arrest delivery for brief periods in order to undertake other therapeutic measures. Tocolytic agents that are currently in use for inhibiting contractions include xcex22-adrenergic agonists, magnesium sulfate, ethanol, and inhibitors of prostaglandin synthesis, such as indomethacin. The use of tocolytic agents has been reviewed in several symposia (Symposium, 1981, 1982) and by Caritis (1983).
In the current practice of obstetrics, the use of indomethacin, which is an enzyme inhibitor, to inhibit prostaglandins in the treatment of premature labor prior to 33 weeks of gestation, is an accepted medical practice. However, enzyme inhibitors of prostaglandin synthesis, such as indomethacin, can unnecessarily prolong gestation in term pregnancies. In addition, the use of indomethacin in premature labor has been curtailed because of concern for its potential for causing adverse effects in the fetus. Of particular importance is the possibility of premature closure of the ductus arteriosus and the production of pulmonary hypertension from use of indomethacin. In addition, relatively high molar concentrations of indomethacin are necessary to produce pharmacological affects, on the order to at least 10xe2x88x923 molar (M).
For example, the indiscriminate inhibition of several vasodilatory and vasoconstrictive prostanoids by indomethacin (prostaglandin E2, prostaglandin F2xcex1, prostacyclin, thromboxane A2) is believed to be related to the incidence of serious complications to mother and fetus from the use of this agent in vivo. For example, inhibition of prostacyclin in the pregnant animal can result in vasoconstriction; while inhibiting PGE can result in premature closure of the fetal ductus arteriosus. While fetal echocardiography can detect early signs of constriction of the ductus arteriosus, and its use may permit the continued administration of indomethacin or related agents in those instances where evidence of ductal construction is absent (Moise et al., 1988), the risk of these serious side effects make the treatment undesirable. The potentially serious side affects observed with currently employed regimens for managing labor, particularly with the use of indomethacin through the control of prostaglandin synthesis, continues to prompt research efforts to identify the mechanisms involved in the onset and progression of labor.
Prostanoids are a family of autacoids (formed from arachidonic acid) thought to play an important role during implantation, in the progress and maintenance of pregnancy, and during the initiation and progress of labor (Angle and Johnston, 1990). Placental prostanoid production is considered to be important during labor as well as throughout pregnancy, in regulating vascular tone, as well as affecting other hormonal production (Myatt, 1990). In human pregnancy, multiple sites of chorionic prostanoid production have been identified, i.e., the amnion, the chorion, the decidua and the placenta (Duchesne et al., 1978; Mitchell et al., 1978a, 1978b, 1978c; Robinson et al. 1979; Haning et al., 1982; Olson et al., 1983; Harper et al., 1983; Siler-Khodr et al., 1986b). In addition to its role in prostanoid production, the placenta also has multiple paracrine and endocrine capacities in human pregnancy. Although it is recognized that prostanoids such as prostaglandin E2, prostaglandin F2xcex1, the metabolite of PGF2xcex1, 13,14-dihydro-, 15-keto-prostaglandin F2xcex1 (PGFM), thromboxane A2 (TXB2) and prostacyclin (PGl2) are all produced by placental tissue, the quantities of these substances, relative to the size of the placenta is frequently not appreciated. In addition, while the placenta is known to be an important site of prostanoid production, little is known of factors controlling the production of these prostanoids from human placental tissues.
Abnormal placental prostanoid production has been reported in diseases of pregnancy, including pregnancy-induced hypertension and intra-uterine growth retardation (Demers and Gabbe, 1976; Robinson et al., 1979; Hillier and Smith, 1981; Valenzuela and Bodhke, 1980; Jogee et al., 1983; Walsh, 1985). However, very few studies have been done on the control of human placental prostanoid release.
Insulin like growth factor (IGF-I), also commonly known as somatomedin-C, is a growth factor that is well known for its stimulation of cellular proliferation, and is recognized as the principal mediator of the action of growth hormone. (Murphy et al. (1990), Endocrine Reviews, 11(3): 443-453)). The IGFs are known to circulate in relatively high concentrations in the body, despite the fact that they are synthesized in many, if not most, tissues. The known activity of IGF-I in mediating growth hormone is consistent with the observation made by others that it may enhance fetal growth. IGF-I, however, has not been described as important in the onset or during the progression of labor, and therefore, the use of IGF-I during labor has not been examined. Nor has IGF-I been described as related to the activity of prostaglandins or prostanoids.
The present invention provides improved methods for managing pre-term labor, as well as for inducing labor, in for example post-term pregnancies, without the potential for risk to the fetus or mother associated with use of other common pharmaceutically used drugs that modulate prostaglandin production, such as indomethacin.
Insulin like growth factor I (IGF-I) is a hormone that is demonstrated by the present inventor to be particularly useful at relatively low molar concentrations, on the order of 10xe2x88x929 molar, in producing a selective pharmacological affect on human placental tissue.
More specifically, IGF-I is demonstrated to provide a specific and effective inhibition of the production of particular vaso-constrictive chorionic prostanoids, particularly thromboxane and prostaglandin F2xcex1 by human placental cells, without inhibiting the production of vaso-dilating prostanoids, such as prostacyclin (PGI) or prostaglandin E2. The disadvantages of non-specific inhibition of prostaglandin E2 and high pharmacologically effective molar concentrations associated with the use of enzyme inhibitors, such as indomethacin and indomethacin-like analogs are therefore avoided. The methods may be used for regulating the production of vasoconstrictive prostanoids from chorionic tissues, such as the amnion, the chorion and the placenta. In addition, analogs of IGF-I and IGF-II are anticipated to provide the specific prostanoid regulation from chorionic tissues in conjunction with the claimed invention.
In one aspect of the present invention, a method for selectively regulating chorionic cell, particularly placental cell, production of thromboxane and prostaglandin F2xcex1 is provided. The method most preferably comprises treating placental cells with a pharmacologically effective amount of insulin like growth factor (IGF-I) or an analog thereof. For purposes of describing the present invention, a pharmacologically acceptable concentration of IGF-I is defined as an amount sufficient to inhibit thromboxane and prostaglandin F2xcex1 production by placental cells without inhibiting or otherwise affecting placental prostaglandin E2 or prostacyclin (PGI) production. While inhibition of thromboxane and prostaglandin F2xcex1 production will occur upon treatment with IGF-I, production of prostaglandin E2, human chorionic gonadotropin and PGFM will remain unaffected.
It is anticipated that either IGF-I, IGF-II, or analogs of these agents, may be employed in the described methods. However, IGF-I is most preferred. The described method may be employed to regulate production of chorionic thromboxane and PGF2xcex1 in any variety of placental cells, such as those of farm or domesticated animals or humans. In a most preferred embodiment, the claimed method provides for the regulation of human chorionic tissue prostanoid production, particularly by human placental cells.
In this particular aspect of the invention, a pharmacologically effective concentration of insulin like growth factor, particularly IGF-I, effective to inhibit thromboxane production by human placental cells in vivo is defined as an amount sufficient to achieve a concentration of between about 10xe2x88x927 to about 10xe2x88x9210. This amount constitutes a pharmacologically active dose that is well within physiological ranges, and therefore can be readily used by the artisan of ordinary skill in pharmacy as a basis for defining an appropriate dose to be used in vivo as part of an appropriate human dose regimen.
In still another embodiment of the invention, a method for inhibiting labor by inhibiting the production of thromboxane and prostaglandin F2xcex1 by placental cells is provided. The method most preferably comprises administering to a pregnant animal a pharmacologically effective amount of insulin like growth factor sufficient to inhibit the production of thromboxane (TxB2) and prostaglandin F2xcex1 by chorionic cells without affecting prostacyclin, prostaglandin E, PGFM, and human chorionic gonadotropin (hCG) production.
While the claimed method may be useful in the treatment of any variety of animals, the present inventor contemplates the particular utility of the method in the treatment of premature labor in humans. Specifically, spontaneous labor prior to between about 20 and about 34 weeks gestation in a pregnant human female may be inhibited employing the present method by administering a pharmacologically effective dose of a clinical grade insulin like growth factor I (IGF-I) to the patient. Clinical grade insulin like growth factor (IGF-I or IGF-II), particularly IGF-I and IGF-II made by recombinant techniques are available from pharmaceutical suppliers, such as for human use. The dose of insulin like growth factor to be administered to the patient will vary depending upon the particular circumstances of the patient being treated, for example, the mode or delivery (vaginal, C-section), the weight of the pregnant female, and the particular gestational age of the fetus. The IGF-I or IGF-II would be given to the patient until clinical indications of the labor subsiding, such as cessation of contractions or halted cervical dilation and effacement is observed by the attending physician. These parameters are well known to those of skill in the obstetrical arts, as is the determination of appropriate doses to administer to a patient given the disclosure provided herein.
It is contemplated that a pharmacologically effective amount of insulin like growth factor, IGF-I, sufficient to inhibit thromboxane production by placenta in a pregnant human female will generally be an amount sufficient to achieve a concentration of between about 5 ng/ml to about 80 ng/ml in the amniotic fluid surrounding the fetus or umbilical cord blood of the fetus. Insulin like growth factor may be administered to the patient by any variety of routes, for example, subcutaneously, intramuscularly, intravenously, or intra-amniotically. Most preferably, the insulin like growth factor is to be administered to the patient intra-amniotically. The insulin like growth factor-I (IGF-I) may be administered to the patient as it is obtained from the pharmaceutical supplier in a pharmaceutically acceptable carrier solution, or may be diluted to a desired dosage with pharmaceutically acceptable carrier solutions generally available from pharmaceutical suppliers. Clinical grade preparations of IGF-I and IGF-II are available for use in humans in conjunction with the practice of the present invention.
The present disclosure also provides a method for inducing labor in a pregnant animal. According to one embodiment of the method, labor is to be induced by inhibiting IGF-I in the animal, which would be expected to result in a concomitant increase in the production of thromboxane and PGF2xcex1 from chorionic tissues, particularly placental cells. The present inventor contemplates that these physiological events may be accomplished by administering a pharmacologically effective amount of a specific inhibitor of insulin like growth factor-I (IGF-I) or insulin like growth factor-II (IGF-II) to the pregnant animal.
By way of example, specific inhibitors of insulin like growth factor IGF-I or IGF-II include antibodies having specific binding affinity for IGF-I or IGF-II. While both polyclonal and monoclonal antibodies may be employed for such use, monoclonal antibodies are most preferred. By way of example, a monoclonal antibody specific for IGF-I may be prepared according to standard hybridoma preparation techniques as outlined in the present disclosure. Other specific inhibitors of insulin like growth factor that are contemplated by the present inventors to be useful in the described method for inducing labor include synthetic antagonists of IGF-I or IGF-II, and metabolizing enzymes of IGF-I or IGF-II. Specific inhibitors of IGF-I may be administered to an animal through any variety of routes, including subcutaneous, intramuscular, or intravenous administration, as described above.
In practice, the attending physician would administer an inhibitor of insulin like growth factor (such as IGF-I, IGF-II) to a pregnant female of at least 40 weeks gestational age, or to a female of lesser gestational age medically where indicated, and continue to administer the IGF-I or IGF-II inhibitor until clinically recognized symptoms of the onset of labor are observed, such as the onset of contractions or dilation of the cervix effacement.
It is anticipated that the described method may be particular efficacious in the treatment of pregnant human females having progressed beyond about 42 weeks gestational age, or in those situations where the induction of labor is otherwise medically indicated for the safety of the mother and/or child. Again, the specific inhibitor of insulin like growth factor would be administered to the pregnant female until contractions commence and/or until the observation of other clinically recognized signs of labor onset, such as dilation of the cervix or effacement.
Standard gynecological and obstetrical clinical procedures well known to those of skill in the obstetrical art would be employed in the application of the herein disclosed methods for both inhibiting and inducing labor, as well as in the treatment of gestational hypertension, given the present disclosure of the specific activity of the insulin like growth factor I on human placental cells, and the specific inhibitory effect that IGF-I and IGF-II inhibitors are anticipated to have on chorionic tissue prostanoid production.
The present invention also provides methods for regulating vasoconstriction through the administration of insulin like growth factor, such as IGF-I or IGF-II, or analogs thereof. IGF-I is most particularly preferred for this use. This method would be particularly efficacious for the treatment of gestational hypertension in a pregnant human female. Again, the specific inhibitory activity of IGF-I on placental tissue production of vasoactive prostanoids, such as thromboxane and prostaglandin F2xcex1, provides a potentially powerful clinical tool in the management of this pathology without the undesirable side effects associated with other non-specific prostanoid inhibitors.
The following abbreviations are employed throughout the description of the present invention:
DMSO=Dimethyl sulfoxide
PGE=prostaglandin E 6-Keto - PGF1xcex1=6-keto prostaglandin F1xcex1
PGFM=13, 14,-dihydro-15 keto-prostaglandin F
BSA=Bovine serum albumin
EDTA=ethylene diamino tetraacetic acid
U=Units
TXB2 Thromboxane B2 
IGF-I=Insulin like growth factor-I
PGF=prostaglandin F
PGI=prostacyclin
NDGA=Tordihydroguaiaretic Acid